A tumor marker is a biochemical indicator for the presence of a tumor. As used herein, a "tumor marker" refers to a tumor-derived molecule that can be detected in tumor tissue, plasma or other body fluids.
Tumor markers are used in clinical medicine in the diagnosis and mapping of cancer, to determine response to therapy and as an indication of relapse during the follow-up period. Histopathologic diagnosis of cancer can include the immunochemistry techniques developed for detecting tumor markers in tissue biopsies, relying on the use of antibodies which bind preferentially with the marker. In radioimmunoimaging and radiotherapy, radiolabeled or tagged antibodies are used for locating and mapping metastases or delivering lethal irradiation locally to the tumor. These methods rely on the selective binding of antibodies with tumor markers.
Tumor markers which have proven to be clinically useful for cancers include alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin, calcitonin, prostatic acid phosphatase, CA-125 and immunoglobulins. Each marker has been found useful for certain specific cancers. Newly discovered protein tumor markers include prostate-specific antigen (prostate cancer) and tumor-associated antigen (TA-4) (uterine cervix). In addition, investigations for cancer markers produced by oncogenes have expanded. One limitation of the markers found to date is their presence, at some level, in non-tumor tissues. As a consequence, serum tumor marker panels are suggested for more reliable diagnosis of certain cancers. Another limitation in the current technology is the absence of reliable markers for certain general types of cancers such as adenocarcinomas.
The promise of monoclonal antibodies (MAbs) for improved diagnosis and therapy of cancer is evidenced by a growing number of trials using mouse MAbs to cancer-associated antigens as reagents for serologic diagnosis, imaging and therapy. MAb variable regions possess significant informational content, potentially conferring enhanced selective capability when compared to conventional modes of cancer diagnosis and therapy. However, the in vivo clinical use of mouse MAbs may be limited, since a substantial proportion of patients who have received parenteral mouse MAbs produce an anti-mouse Ig response. Such a response occurs more frequently after multiple administrations, may occur despite immunosuppressive therapy and may result in adverse clinical sequelae as well as abrogation of the intended diagnostic or therapeutic effect. Efforts to reduce the immunogenicity of mouse MAbs include the utilization of antibody fragments or the creation of genetically engineered chimeric human-mouse MAbs.
Human MAbs (hMAbs) would appear to be an attractive solution to the MAb immunogenicity problem. HMAbs have been considered more difficult and costly to generate than mouse MAbs, and relatively few examples of well characterized HMAbs to cancer-associated antigens have been described. Human serologic studies have revealed that a spectrum of types of human cancer-associated antigens are immunogenic, including examples of antigens which are (i) highly specific but only found in individual tumors ("Class I", e.g., idiotypes of B-cell lymphomas), (ii) highly nonspecific antigens also found among many normal tissues ("Class III", e.g., blood group antigens), or (iii) expressed by tumor cells of similar histogenesis but in a restricted or trace distribution among normal cells ("Class II", e.g., differentiation antigens). The reactivity of HMAbs derived from cancer patient lymphocytes appears to recapitulate this spectrum of specificity and suggests that HMAbs of intermediate (Class II) specificity could be produced and utilized to detect antigens shared by cancer cells, but sparingly expressed by normal cells. Although not perfectly specific, such HMAbs could still prove useful for clinical application depending on the distribution of the target antigens among normal tissues.